Could aldosterone gone bad be the cause of ccsvi and ms?

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby 1eye » Sat Dec 08, 2012 10:24 pm

I didn't agree with the paper on homeostasis. Although I do believe evolution has produced amazing abilities such as long-distance bird migration and camouflage morphing in some animals, and that the control systems in our bodies sometimes cooperate and/or combine, I think homeostasis is generally automatic. I also agree there is no one stable state it is seeking.

It is a normal function of feedback control systems to adapt to changes in external conditions (often referred to as 'signal'). A servo is an example of such a control. If it were cognitively controllable, my wife would surely not get any hot flashes. Cognition can be brought to bear in deliberately changing some things, but they are not often internal and automatic as well as internal and consciously controllable; more often, control is effected by seeking a different external environment, for instance an air-conditioned one, or a sugar-free soda.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Sun Dec 09, 2012 9:12 am

Upon reading that paper again this morning with a fresh brain, I paid more attention to the parts which seemed like a puffed up rant rather than presentation of theory (therefore unworthy of my attention last night.) You are correct. Large parts of the allostasis theory as it was presented seem half baked/farfetched.

But since you seem to have a great interest in the concept of homeostasis and negative feedback loops, here are a few more links for your reading pleasure. I'm relying on your greater understanding to muck through this mess and see if it could play a part...the last link seems most interesting to me.

http://www.ncbi.nlm.nih.gov/m/pubmed/16 ... 79/related

http://www.ncbi.nlm.nih.gov/m/pubmed/19 ... 79/related

http://www.ncbi.nlm.nih.gov/m/pubmed/12 ... 34/related

http://www.sciencedirect.com/science/ar ... 0605002644

http://content.karger.com/ProdukteDB/pr ... 323953.pdf

When I'm clear of this flagyl, I'll have to revisit this topic. Does this homeostasis/negative feedback loop allow for short or long term adjustments based on changes in physiological conditions like those mentioned in the ischemia paper I read?

Taking a break for now...my browser tabs are maxed out on 3 devices and my brain can't keep up!
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby 1eye » Sun Dec 09, 2012 1:46 pm

I liked the fourth paper because although there is no good set of diagrammatic principles dedicated to medical science, that doesn't stop some people from trying to use visual simplifications and elaborations.

The arrow on the far right of figure 4 shows how, in the skin, stress can directly affect the endothelial leakage being caused by factors that are released (by mast cells?) under stress.

These factors are released in other ways too, I imagine. Is it always caused by some form of stress? I think I understand why TNF causing this vascular leakage can be good, if there are tumours with a lot of broken vasculature, and perhaps that's part of the dichotomy between MS and cancer: too much TNF can be harmful to non-tumor growth, so it may be less likely when other things are already causing leakage across the BBB. I think I read it is released during exacerbations.

Maybe it's not always a good solution, when the stimulus for the release of TNF is removed completely, not allowing normal necrosis to occur. Sounds blasphemous.

I agree that it is easily possible for things that stabilize and improve things in the short term to be unnoticed long-term destroyers. It makes me think of Al Gore's frog example.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Mon Dec 10, 2012 9:47 am

Wow. I can't believe how well this fits...

Personal history: Years and years of high chronic stress.

Chronic stress can alter your bodies hypothalamus-pituitary-adrenal function/regulation. Most studies focus on cortisol in the process but aldosterone is also greatly affected in this case.
http://content.karger.com/ProdukteDB/pr ... 323953.pdf
Studies on MS Onset
In the study by Liu et al. [23] , MS patients reported
more negative life events and family problems and less
utilization of social support 3 years before disease diagnosis
than healthy controls. The MS group suffered more
often from negative emotions such as symptoms of depression,
anxiety, obsession, phobia, tense interpersonal
relationship and somatization disorder, all of which were
positively correlated with negative life events and family
problem scores, and negatively with utilization of social
support. Personality did not differ among groups. In a
large retrospective cohort study in the Danish population,
parents who had lost a child younger than 18 years
were at greater risk of MS (hazard ratio, HR: 1.56; 95% CI:


http://www.fatiguesymposium.ca/pdf/Just ... static.pdf
Page 3 of 15 in this document shows graphical illustration of different physiological responses to stress. Prolonged response could lead to chronically elevated aldosterone.
3. Allostatic load model
Allostatic load (AL) represents the ‘wear and tear’ the body
experiences when repeated allostatic responses are activated
during stressful situations (McEwen and Stellar, 1993). Real or
interpreted threats to homeostasis initiate the sympathetic–
adrenal–medullary (SAM) axis release of catecholamines and the
hypothalamic–pituitary–adrenal (HPA) axis secretion of glucocorticoids
that mobilize energy necessary for fight-or-flight responses
(Sapolsky et al., 2000). Coordination of allostasis therefore depends
on the brain’s evaluation of threat (hippocampal, amygdaloid, and
prefrontal cortical regulation); (Herman et al., 2005; McEwen,
2007) and execution of physiological responses. The perception of
threat and mobilization of these allostatic mechanisms are
fundamentally shaped by individual differences in constitutional
(genetics, development, experience), behavioral (coping and
health habits), and historical (trauma/abuse, major life events,
stressful environments) factors that ultimately determine one’s
resiliency to stress (Fig. 1; McEwen, 1998a).
While adaptive acutely, chronic over-activation of SAM- and
HPA-axis products induce a ‘domino effect’ on interconnected
biological systems that overcompensate and eventually collapse
themselves, leaving the organism susceptible to stress-related
diseases (Korte et al., 2005; Lupien et al., 2006; McEwen, 1998b).
Brain changes associated with chronic stress and AL (e.g., synaptic
and dendritic remodeling, suppressed neurogenesis, structural
atrophy/hypertrophy) further diminish the body’s ability to
cognitively process and physiologically respond to stressors
(McEwen, 2000b). These contribute to pathophysiological allostatic
states (Fig. 2) that reflect response patterns in which allostatic
systems are overactivated and/or dysregulated (McEwen, 2003b).
These processes are rooted in biopsychosocial antecedents
integrated within the AL model that postulates a sequential chain
of dysregulation in multiple systemic mediators.
A key feature of allostasis, AL, and ultimately allostatic overload
is that multiple mediators of adaptation are involved and
interconnected in a non-linear network. Each mediator system
produces biphasic effects and is regulated by other mediators,
often in reciprocal fashion, leading to non-linear effects upon many
organ systems of the body (McEwen, 1998a). At first, prolonged
secretion of the stress hormones epinephrine, norepinephrine, and
cortisol (antagonized by dehydroepiandosterone) can falter in
their ability to protect the distressed individual and instead begin
to damage the brain and body (McEwen, 2006a). Stress hormones
and their antagonists, in conjunction with pro- and antiinflammatory
cytokines (e.g., interleukin-6, tumor necrosis factor-
alpha) represent the AL biomarkers referred to as the primary
mediators (McEwen, 2003b). Synergistic effects of these molecules
exert primary effects on cellular activities (enzyme, receptor, ion
channel, genomic) that compromise the physiological integrity of
allostatic mechanisms. Over time, subsidiary biological systems
compensate for the over and/or under production of primary
mediators and in turn shift their own operating ranges to maintain
abated chemical, tissue, and organ functions. This prodromal stage
is referred to as the secondary outcomes, whereby metabolic (e.g.,
insulin, glucose, total cholesterol, high density lipoprotein
cholesterol, triglycerides, visceral fat depositing), cardiovascular
(e.g., systolic and diastolic blood pressure), and immune (e.g.,
fibrinogen, c-reactive protein (CRP)) parameters reach sub-clinical
levels. The final stage of AL progression is allostatic overload,
whereby the culmination of physiological dysregulations leads to
disordered, diseased, and deceased endpoints referred to as tertiary
outcomes.
The AL model proposes that by measuring the multi-systemic
interactions among primary mediators and effects, in conjunction
to sub-clinically relevant biomarkers representing secondary
outcomes, biomedical advances can be made in the detection of
individuals at high risk of tertiary outcomes (McEwen, 2000a;
McEwen and Seeman, 1999). Physicians routinely incorporate
many of these biomarkers already, except attention is largely
placed on values reaching clinically significant levels. By incorporating
and integrating additional biomarkers, identifying preclinical
values, and triangulating methods with various other
measures if feasible (e.g., psychosocial, genotypes, and phenotypes),
greater prediction of pathologies can be achieved. Because
mediators leading to AL and disease susceptibilities interact in a
non-linear manner whereby fluctuations in values induce compensatory
remediation over time (Fig. 3), delineating time-courses
of dysregulation is difficult (McEwen, 2008). Quantifying AL at a
biological level, let alone with respect to the multiplicity of
psychosocial modulators has thus represented a significant
challenge. Nonetheless, advances over the last decade have helped
pave the way to a greater understanding of the winding road to AL.



http://www.sciencedirect.com/science/ar ... 340900102X
Aldosterone: A forgotten mediator of the relationship between psychological stress and heart disease
Laura D. Kubzanskya, b, , ,
Gail K. Adlera, b


Abstract

Numerous studies support the notion that cumulative exposure to chronic stress is a risk factor for cardiovascular disease (CVD). Various stress-related hormones have been proposed as potential mediators of the relationship between psychological stress and CVD, including catecholamines and more indirectly, cortisol. Somewhat surprisingly, although aldosterone is also released in response to hypothalamic–pituitary–adrenal (HPA) axis activation, it has not been considered as relevant for this relationship. In the present review we will consider aldosterone as a potentially important mediator of the relationship between negative affective states and CVD. First, we will briefly review the known functions and roles of aldosterone, and then consider its actions in both the brain and the periphery. We will then review the available literature on the role of aldosterone in CVD, and also consider links between aldosterone and various forms of chronic psychological stress. Finally we will present an integrated model of how aldosterone may mediate effects of chronic stress on CVD, recommend new directions for research, and identify important methodological and design issues for this work.
Image
Fig. 1. Effect of ACTH infusion on serum levels of cortisol (μg/dl) (open circles) and aldosterone (ng/dl) (squares). 13 healthy pre-menopausal women on ad lb diets received an intravenous infusion of ACTH at sequential doses of 0.00, 0.00, 0.05, 0.15, 0.50, 1.50 and 5 mIU/kg/30 min. 24 h urinary sodium levels were (156 ± 24 mEquib./24 h). Cortisol data was reported previously (Adler et al., 1999).
Image
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Aldosterone gone bad is not the sole cause of ccsvi and ms

Postby MarkW » Mon Dec 10, 2012 10:02 am

Anonymoose wrote:
MarkW wrote:Anonymoose asks: Could aldosterone gone bad be the cause of ccsvi and ms?
Highly unlikely that MS has one cause. A factor in MS in some people is
possible as there appears to be many factors involved in MS.
MarkW

You don't find it odd that so many of the MS related factors/cofactors/mysteriously successful treatments can be associated with aldosterone? If there are factors I am missing please do point them out because I want to know if aldosterone is the cause or not.

If you want to understand the factors involved in MS then I suggest you start with the following:
1-Genetics. Our genome controls how we turn out as human beings. Over 50 genes/groups of genes are associated with MS. Then there is epi-genetics to study and add to the equation. Big subject.....
2-Immunity. Neurologists have spent over 50 years saying (auto)immunity is the one and only cause of MS. They are wrong as there are other factors. Nevertheless our immune systems are a major factor in MS.
3-Environment. Many factors could be mentioned here: Hormones/Viruses/Bacteria/Diet/etc etc

CCSVI probably fits into genetics/epi-genetics but for me that is far less important than treating known symptoms (low Vit D3=very cheap, stenosed valves=fairly expensive).
I strongly recommend treating the MS factors you can afford to (or your insurance will pay for) rather than waiting for the cause(s) of MS to be identified.

Best wishes in your study, try to see the big picture.
MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Aldosterone gone bad is not the sole cause of ccsvi and

Postby Anonymoose » Mon Dec 10, 2012 10:15 am

MarkW wrote:
Anonymoose wrote:
MarkW wrote:Anonymoose asks: Could aldosterone gone bad be the cause of ccsvi and ms?
Highly unlikely that MS has one cause. A factor in MS in some people is
possible as there appears to be many factors involved in MS.
MarkW

You don't find it odd that so many of the MS related factors/cofactors/mysteriously successful treatments can be associated with aldosterone? If there are factors I am missing please do point them out because I want to know if aldosterone is the cause or not.

If you want to understand the factors involved in MS then I suggest you start with the following:
1-Genetics. Our genome controls how we turn out as human beings. Over 50 genes/groups of genes are associated with MS. Then there is epi-genetics to study and add to the equation. Big subject.....
2-Immunity. Neurologists have spent over 50 years saying (auto)immunity is the one and only cause of MS. They are wrong as there are other factors. Nevertheless our immune systems are a major factor in MS.
3-Environment. Many factors could be mentioned here: Hormones/Viruses/Bacteria/Diet/etc etc

CCSVI probably fits into genetics/epi-genetics but for me that is far less important than treating known symptoms (low Vit D3=very cheap, stenosed valves=fairly expensive).
I strongly recommend treating the MS factors you can afford to (or your insurance will pay for) rather than waiting for the cause(s) of MS to be identified.

Best wishes in your study, try to see the big picture.
MarkW


I most respectfully must ask if you have read any of the studies/excerpts I have posted? You keep telling me I am looking in the wrong place (and I very well may be). How can you make such an assumption without considering and studying the theory and supporting evidence I am throwing out here?
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Tue Dec 11, 2012 8:47 am

HPA axis disregulation and MS progression. This abstract refers solely to cortisol reaction to ACTH. However, as noted earlier in thread, aldosterone increases in reaction to ACTH at about the same rate as cortisol.

http://www.neurology.org/content/53/4/772.short
Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS

F. Then Bergh, MD,
T. Kümpfel, MD,
C. Trenkwalder, MD,
R. Rupprecht, MD and
F. Holsboer, MD, PhD

+ Author Affiliations

From the Max Planck Institute of PsychiatryNeurology, Muenchen, Germany.

Address correspondence and reprint requests to Dr. Florian Then Bergh, Neurologische Klinik, Klinikum Grosshadern, Marchioninistr. 15, D-81377 Muenchen, Germany.


Abstract

Objective: To investigate whether dysregulation of the hypothalamo–pituitary–adrenal (HPA) axis is related to clinical characteristics in MS.

Methods: The authors performed the combined dexamethasone–corticotropin-releasing hormone test (Dex-CRH test) in 60 MS patients and 29 healthy control subjects. In addition, the short adrenocorticotropic hormone (ACTH) test was performed in 39 consecutive patients. All patients had active disease and none were treated with glucocorticoids, immunosuppressants, or immunomodulators.

Results: The patients had an exaggerated rise in plasma cortisol concentrations in the Dex-CRH test (p < 0.05), indicating hyperactivity of the HPA system. The degree of hyperactivity was moderate in relapsing–remitting MS patients (n = 38; area under the time-course curve for cortisol [AUC-Cort] 226.2 ± 38.9 arbitrary units [AU], mean ± SEM), intermediate in secondary progressive MS patients (n = 16; AUC-Cort, 286.8 ± 60.2 AU), and marked in primary progressive MS patients (n = 6; AUC-Cort, 670.6 ± 148.6 AU). Differences were significant between the three patient groups (p < 0.005), and between control subjects (n = 29; AUC-Cort, 150.8 ± 34.1 AU) and each patient group. Indicators of HPA axis activation correlated with neurologic disability (Kurtzke’s Expanded Disability Status Scale), but not with the duration of the disease, number of previous relapses, previous corticosteroid treatments, or depressed mood (Hamilton Depression Scale). The ACTH test was normal in 31 of the 33 patients studied.

Conclusion: HPA axis hyperactivity in MS is related to the clinical type of disease, with a suggestion of increasing HPA axis dysregulation with disease progression.
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Aldosterone gone bad is not the sole cause of ccsvi+MS

Postby MarkW » Tue Dec 11, 2012 10:08 am

Anonymoose wrote:......ask if you have read any of the studies/excerpts I have posted? You keep telling me I am looking in the wrong place (and I very well may be). How can you make such an assumption without considering and studying the theory and supporting evidence I am throwing out here?


I read your abstracts with interest and attempt to place them in the big picture of MS. I am challenging your assertion that this one hormone is the cause of CCSVI+MS. It may be a factor in MS but it it mis-leading to say that "Aldosterone gone bad is the cause of ccsvi+ms". You are not looking in the wrong place but having looked in one place you need to explain how this fits into the big picture of MS.
I suggest you read Prof Zamboni's recent paper, in a thread I will bump for you.
MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Aldosterone gone bad is not the sole cause of ccsvi+MS

Postby Anonymoose » Tue Dec 11, 2012 11:01 am

MarkW wrote:
Anonymoose wrote:......ask if you have read any of the studies/excerpts I have posted? You keep telling me I am looking in the wrong place (and I very well may be). How can you make such an assumption without considering and studying the theory and supporting evidence I am throwing out here?


I read your abstracts with interest and attempt to place them in the big picture of MS. I am challenging your assertion that this one hormone is the cause of CCSVI+MS. It may be a factor in MS but it it mis-leading to say that "Aldosterone gone bad is the cause of ccsvi+ms". You are not looking in the wrong place but having looked in one place you need to explain how this fits into the big picture of MS.
I suggest you read Prof Zamboni's recent paper, in a thread I will bump for you.
MarkW


I have not made that assertion. I am merely exploring the idea. I wouldn't feel comfortable saying that aldosterone causes ccsvi and/or ms unless I had seen that medical intervention addressing elevated aldosterone action resulted in long term remission of ms. Even then, I wouldn't say that it is the only possible cause for ms. I will say that, at this point, I do highly suspect that aldosterone may be the culprit. That said, I clearly am no authority on the human body and it's innerworkings so who am I to listen to? I'm posting my findings so people can read, offer input, and come to their own conclusions.

Thank you for bumping Zamboni's paper. It should prove an interesting read today. :) However, I don't want to hyperfocus on ccsvi because I think (this could change after reading his paper) ccsvi is only a component of MS and I am trying to look at a bigger picture. :P

I'd really appreciate your opinion on the specifics I am posting here as you have a much greater understanding of these things than I do.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Tue Dec 11, 2012 12:56 pm

MarkW,

I'm reading Zamboni as you suggested. It's making me "what if." So, I have some what if's for you as I struggle through these papers...

What if the reason why ballooning/stenting the jugular and azygos veins doesn't fix everything is because you are only treating part of the problem causing CCSVI?

What if vascular fibrosis in the brain is contributing to CCSVI?

What if autoregulation of cerebral blood flow is out of wack?

What if concentrating on just those few valves/regions as the cause of CCSVI is making us miss something that could be more monumental in the management of CCSVI?

What if I fall asleep trying to read through this? lol

Edit/update:

Started reading the papers you originally posted then noticed you directed me to a specific link (which was much less sleep inducing), pointing out that Zamboni said MS was multifactoral. I agree in the very least it does appear to be so.

But, if my theory in progress is valid (NOT saying it is), it would be multifactoral just as ms is.

Stress/Infection induction of HPA axis dysregulation(perhaps a genetic tendency for this?)-chronic excess aldosterone-other hormonally induced diseases like hyperinsulinemia-altered metabolism of vitamins/minerals/uric acid-chronic inflammation-breakdown of bloodbrain barrier via several mechanisms (including CCSVI)-increased HPA axis dysregulation-MS progression.

Will keep reading up on Zamboni...
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Tue Dec 11, 2012 4:21 pm

http://phleb.rsmjournals.com/content/25/6/269.full.pdf
Page 274 figure 6 of Zamboni paper

Could aldosterone suppression of baroreflex be the cause of the flatline CSAs in ms patients?

Aldosterone blunts the baroreflex response in man
http://www.clinsciusa.org/cs/095/0687/0950687.pdf
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Tue Dec 11, 2012 7:13 pm

Good Lord! I hate it when I don't see something that is right in front of my face. I didn't realize CCSVI was the exact condition of reduced cerebrospinal flow due to jugular and azygous vein obstruction. What I have been referring to as ccsvi is a condition in which the brain has inadequate cerebrospinal flow for whatever reason, including obstructed jugs and azys.

Based on that, I can't see how aldosterone would cause ccsvi if it is solely the result of valves that are truly congenitally abnormal. I can see how it would cause vein stenosis and reduced cerebrospinal flow. I could also see how improving flow by treating ccsvi could reduce cumulative flow issues in the brain leading to clinical improvement.

Poke me with a fork. I am done for today.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby SaintLouis » Tue Dec 11, 2012 9:00 pm

Interesting papers and food for thought.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Wed Dec 12, 2012 11:16 am

MS-Low Uric Acid-Aldosterone block (eplerenone)

Uric acid levels in MS patients are low, lower during relapse. At appropriate levels, uric acid has neuroprotective qualities, acting as an antioxidant/peroxynitrite scavenger. Aldosterone increases formation of peroxynitrite. Eplerenone, an aldosterone blocker, has been shown to elevate levels of uric acid...possibly because it is not being metabolized as quickly to counteract the aldo-peroxynitrite effect.

http://www.ncbi.nlm.nih.gov/pubmed/11985629
Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction.
Toncev G, Milicic B, Toncev S, Samardzic G.
Source
Center of Neurology, Clinical Hospital Center Kragujevac, Svetozara Markovica, Yugoslavia. gtoncev@ptt.yu

Abstract

Several findings suggest lower levels of serum uric acid in multiple sclerosis (MS) patients. The aim of this study is to investigate relationships of uric acid serum levels in relapse-remitting (RR) MS patients with clinical activity of disease and blood-brain barrier (BBB) condition. Sixty-three definite RRMS patients and 40 controls divided into two groups: 20 healthy donors and 20 patients with other inflammatory neurological diseases (OINDs) were analysed. By using a quantitative enzymatic assay according to the manufacture's protocol and a commercial uric acid standard solution, serum uric acid levels were measured and the results were standardized. To investigate BBB function, magnetic resonance imaging after administration of gadolinium was used. MS patients were found to have significantly lower serum uric acid levels (193.89 +/- 49.05 micromol/l; mean value +/-SD) in comparison with healthy donors (292.7 +/- 58.65 micromol/l; P=0.000) and OIND patients (242.7 +/- 46.66 micromol/l; P=0.001). We found that MS patients with relapse had significantly lower serum uric acid levels (161.49 +/- 23.61 micromol/l) than MS patients with remission (234.39 +/- 41.96 micromol/l; P=0.000) and more over, MS patients with BBB disruption had significantly lower serum uric acid levels (163.95 +/- 26.07 micromol/l) than those with normal BBB (252.48 +/- 25.94 micromol/l; P=0.000). Further, we also found that serum uric acid level independently correlated with disease activity, BBB disruption, and gender. These results indicate that lower uric acid levels in MS patients are associated with relapse and suggest that uric acid might be beneficial in the treatment of MS.

http://www.ingentaconnect.com/content/m ... 3/art00015
Uric acid in multiple sclerosis
Authors: Koch, Marcus; De Keyser, Jacques
Source: Neurological Research, Volume 28, Number 3, April 2006 , pp. 316-319(4)
Publisher: Maney Publishing
Abstract:
Peroxynitrite, a reactive oxidant formed by the reaction of nitric oxide with superoxide at sites of inflammation in multiple sclerosis (MS), is capable of damaging tissues and cells. Uric acid, a natural scavenger of peroxynitrite, reduces inflammatory demyelination in experimental allergic encephalomyelitis. Some studies reported lower serum levels of uric acid in MS patients compared with controls, whereas other studies found no difference. A critical appraisal of these studies favors the view that reduced uric acid in MS is secondary to its peroxynitrite scavenging activity during inflammatory disease activity, rather than a primary deficiency. Serum uric acid levels could be used as a biomarker for monitoring disease activity in MS. Therapeutic strategies aimed at raising serum uric acid levels may have a glial/neuroprotective effect on MS patients.

http://submit.clinsci.org/cs/113/0267/cs1130267.htm
In animal models, aldosterone infusion causes endothelial dysfunction via the generation of ROS (reactive oxygen species) [22–24]. Aldosterone increases expression of NADPH oxidase subunits p22pbox and gp91phox through an MR-dependent mechanism, whereas aldosterone stimulates expression of p47phox mRNA through both AT1 receptor and MR-dependent mechanisms (Figure 2) [25,26]. The resultant generation of ROS leads to the formation of peroxynitrite

http://www.hsc.wvu.edu/Charleston/sop/C ... /jun04.pdf
Uric Acid: Eplerenone produced increases in uric
acid to greater than 9 mg/dL in approximately 0.3%
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Wed Dec 12, 2012 12:36 pm

Anti-TNF therapy is associated with onset and worsening of MS. TNF inhibits aldosterone production. Anti-TNF leads to raised aldosterone leads to MS?

http://www.neurology.org/content/57/10/1885.short
Onset of multiple sclerosis associated with anti-TNF therapy
Nancy L. Sicotte, MD and
Rhonda R. Voskuhl, MD
+ Author Affiliations
From the Division of Brain Mapping (Dr. Sicotte), Department of Neurology (Drs. Sicotte and Voskuhl), UCLA School of Medicine, Los Angeles, CA.
Address correspondence and reprint requests to Dr. Nancy L. Sicotte, 710 Westwood Boulevard, Rm. A135, Los Angeles, CA 90095; e-mail: nsicotte@ucla.edu
Abstract

Therapies aimed at inhibiting tumor necrosis factor (TNF), a proinflammatory cytokine implicated in autoimmune disease are effective, especially for rheumatoid arthritis. We report a patient with new onset MS closely associated with the initiation of anti-TNF therapy for juvenile rheumatoid arthritis. It is possible that the inhibition of TNF triggered MS in this individual.

http://www.neurology.org/content/47/6/1531.short
Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2
B. W. van Oosten, MD, F. Barkhof, MD, L. Truyen, MD, J. B. Boringa, MD, F. W. Bertelsmann, MD, B.M.E. von Blomberg, PhD, J. N. Woody, PhD, H.-P. Hartung, MD and C. H. Polman, MD
+ Author Affiliations
From the Departments of Neurology (Drs. van Oosten, Truyen, Boringa, Bertelsmann, and Polman), Diagnostic Radiology (Dr. Barkhof), and Pathology (Dr. von Blomberg), Free University Hospital, Amsterdam, The Netherlands; Centocor Inc. (Dr. Woody), Malvern, PA; and the Department of Neurology (Dr. Hartung), Julius-Maximilians-University, Wurzburg, Germany.
Received February 23, 1996. Accepted in final form May 7, 1996.
Address correspondence and reprint requests to Dr Polman, Professor of Neurology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

Abstract

There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha) improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory diseases in humans, but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and cerebrospinal fluid (CSF) immunologic status.

We did not notice any clinically significant neurologic changes in either patient.The number of gadolinium-enhancing lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after each treatment.

The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced MRIs.

http://endo.endojournals.org/content/125/6/3084.short
Tumor Necrosis Factor and Interleukin-1 Are Potent Inhibitors of Angiotensin-II-Induced Aldosterone Synthesis*
R. NATARAJAN,
S. PLOSZAJ†,
R. HORTON and
J. NADLER‡
- Author Affiliations
Section of Endocrinology, University of Southern California-Los Angeles County Medical Center Los Angeles, California 90033
Address requests for reprints to: Rama Natarajan, Ph.D., Section of Endocrinology, University of Southern California Medical Center, Room 18632, 2025 Zonal Avenue, Los Angeles, California 90033.

Abstract

Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), mediate many inflammatory and cellular responses. However, the effects of TNF and IL-1 on basal and angiotensin-II (All)-stimulated aldosterone synthesis are not known. We studied the effect of recombinant and purified TNF and IL-1 on basal as well as All-, ACTH-, and K+-induced aldosterone synthesis in isolated rat adrenal glomerulosa cells. Since we have previously shown that All action is mediated by activation of the 12-lipoxygenase (12LO) pathway of arachidonic acid, we also evaluated the effects of these cytokines on the 12LO product 12-hydroxyeicosatetraenoic acid (12HETE) using a validated RIA technique. TNF at 2.5 and 5.0 ng/ml produced a dose-dependent inhibition of All-induced aldosterone synthesis [All, 39.0 ± 3.3 ng/106 cells-h; All plus TNF (5.0 ng/ml), 14.3 ± 1.6; P < 0.001 vs. All; All plus TNF (2.5 ng/ml), 24.7 ± 3.2; P < 0.01 vs. All]. Similarly, TNF at 5.0 ng/ml also attenuated the stimulatory effect of ACTH (10−9 M). However, K+- induced aldosterone synthesis was not altered. TNF also did not alter basal aldosterone levels. All, as previously shown, stimulates 12HETE synthesis (basal, 608 ± 114 pg/105 cells-h; versus All, 1268 ± 197; P < 0.02). TNF at concentrations of 1.0–5.0 ng/ml produced a dose-dependent inhibition of All stimulatory action on 12HETE synthesis [All plus TNF (1.0 ng/ml), 650 ± 26 pg, P < 0.03 vs. All; All plus TNF (5.0 ng/ml), 390 ± 46; P < 0.01 vs. All plus TNF (1.0 ng/ml)]. In addition, 12HETE at 10−8 M completely restored the effects of All during blockage by TNF. Purified human IL-1 (75% β, 25% α) as well as recombinant human IL-1β at concentrations as low as 50 pg/ml inhibited All-induced aldosterone synthesis. IL-1β did not alter ACTHor K+-induced aldosterone synthesis and, in fact, had a tendency to potentiate ACTH effects. These results suggest that the cytokines TNF and IL-1 are potent inhibitors, particularly of All action in the adrenal glomerulosa cell. Therefore, local or systemically produced TNF or IL-1 may be important negative modulators of aldosterone synthesis.
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